One of the first pieces of evidence of the participation of TRPC in myocardial infarction (MI) was proposed using bioinformatic analysis combined with experimental approaches. Zhou et al. [70] demonstrated an increase in the expression of TRPC6, which was experimentally validated in a one-month post-MI rat model, suggesting TRPC6 as a potential therapeutic target for MI. Later, other studies highlighted the induction of TRPC proteins under MI and explored the idea that Ca²⁺ influx through TRPC channels overexpressed after MI contributes to cardiac dysfunction and adverse remodeling. In fact, significant increases in TRPC1, 3, 4, and 6 mRNA levels in mice one, two, and six weeks post MI were observed, as compared with sham [71]. This channel upregulation correlates with the increase in Ca²⁺ entry when myocytes isolated from MI adult mouse are stimulated with cyclopiazonic acid and OAG. Furthermore, mice expressing dn-TRPC4 have less pathological hypertrophy, better cardiac hemodynamic performance, and increased survival after MI, as compared with WT mice [71]. Therefore, the loss of TRPC4 function likely protects against the progression of cardiac dysfunction after MI. Interestingly, Jung et al. [72] suggested that gain of function of TRPC4 due to a genetic variation (I957V) causes an increase in channel activity, which has a protective effect against MI. The authors identified a single-nucleotide polymorphism (SNP) in TRPC4 that associates with MI risk in a case–control study. They further used multivariate analysis to show a protective effect of the I957V allele against MI risk, but only in diabetic patients. Therefore, the mutated TRPC4-I957V is thought to mediate higher Ca²⁺ signals, perhaps to facilitate the generation of endothelium and nitric oxide-dependent vasorelaxation. Nevertheless, the authors did not experimentally test this hypothesis. Recently, we observed significant dysregulation in the expression of several TRPC isoforms in a Wistar rat model of MI induced by transient ligation of the left coronary artery. A PCR-based micro-array, qRT-PCR, and Western blotting demonstrated significant upregulation of TRPC1, 3, 4, 5, and 6, whether in at-risk or in remote zones of infarcted hearts, as compared to sham. Specific downregulation of TRPC5 in MI rats infused with urocortin-2 at the onset of reperfusion was observed, offering a role of TRPC5 in cardioprotection [13].

In the case of TRPC3 and 6, a previous study determined that TRPC6 KO mice had significantly higher rates of mortality due to ventricular wall rupture throughout 3–7 days post MI [37]. In contrast, TRPC3/6/7 triple-KO mice subjected to transient MI (30 min of ischemia followed by 24 h reperfusion) exhibit reduced infarct size, better cardiac performance, and less cardiac tissue damage post MI, as compared with WT animals. In addition, they have reduced apoptosis through the inhibition of the calcineurin–nuclear factor of activated T cells (NFAT) signaling pathway [24]. These results suggest that TRPC3, 6, and 7 contribute significantly to worsening MI impacts on cardiac function. Further investigations will be welcome to clarify the discrepancy between these KO studies. It will be interesting to examine whether the cardioprotective effects observed in the triple-KO mice affect the transformation of myofibroblasts required during wound healing and scar formation.

Ischemia and reperfusion (I/R) injury is the main cause of cell apoptosis and necrosis observed after an MI. Several studies demonstrated evidence linking cytosolic Ca²⁺ increase through TRPC and apoptosis after I/R [24,73]. Studies using TRPC inhibitors examined their role in I/R injuries. For instance, Kojima et al. [74] showed, in a Langendorff-perfused mouse heart under I/R, that left-ventricular functions are significantly improved by the administration of ion channel blockers (2-aminoethoxydiphenyl borate (APB) and La³⁺) during the initial 5 min of reperfusion, suggesting a TRPC channel role in contractile dysfunction in reperfused ischemic myocardium. In an atrial cardiac cell line, H9C2, the addition of SKF96365, another widely used inhibitor of TRPC, ameliorates injuries induced by hypoxia–reoxygenation (H/R) [24]. However, it is well known that 2-APB and La³⁺, as reviewed previously [75,76], as well as SKF96365 [75,76], are not specific to TRPC channels and may block other cationic channels. Therefore, these results should be supported by experiments using siRNA and/or TRPC-deficient mice. Actually, other reports used different molecular approaches to identify TRPC isoforms responsible for Ca²⁺ entry and its relationship with cardiac myocyte death under I/R. For example, Shan et al. [73] observed that transgenic mice overexpressing TRPC3 in myocardial cells are highly sensitive to injuries after I/R as they enhance apoptosis through increased TRPC3-mediated Ca²⁺ influx and calpain cleavage. They also demonstrated significant improvement in the viability of cardiomyocytes after SKF96365 treatment. Moreover, Meng et al. [77] observed that in vitro I/R increases TRPC6 protein expression, [Ca²⁺]_i levels, and cell apoptotic rate in a time-dependent manner in H9C2 cell line. In addition, they suggested TRPC6 as a possible target for cardioprotection in H9C2 cells since the administration of danshensu, an active component of Salvia miltiorrhiza, protects against I/R injury by reducing TRPC6 expression via the c-Jun N-terminal kinases (JNK) signaling pathway [77]. Hang et al. [78] also demonstrated that brain-derived neurotrophic factor (BDNF) protects against MI and inhibits H/R-mediated cardiomyocyte apoptosis through TRPC3 and TRPC6 regulation.

On the other hand, the role of TRPC1 in I/R is still unclear. A recent study suggested that it is implicated in I/R injury, as the expressions of mRNA and protein of TRPC1, Orai1, and STIM1 are significantly increased in vivo in mice subjected to myocardial I/R injury and in vitro in H9C2 cells after H/R [79]. Interestingly, the suppression of STIM1 by siRNA decreases the expression of TRPC1 and Orai1, leading to decreased intracellular Ca²⁺ accumulation and apoptosis produced by H/R in H9C2 cells [79]. Therefore, STIM1 likely regulates the expression of TRPC1 and Orai1 in the context of apoptosis and myocardial I/R injury. In contrast, Al-Awar et al. [80] speculated that TRPC1 plays a cardioprotective role against I/R injury. They showed that sitagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), decreases the infarct size in a rat model of I/R which correlates with the increase in protein levels of TRPC1, TRPV1, and calcitonin gene-related peptide in heart tissue. Nevertheless, a specific experiment targeting TRPC1 was not shown. Our recent study, through Western blot, confirms that TRPC1 and 6 are upregulated in a rat model of I/R although they are not inhibited by urocortin-2-mediated cardioprotection. In contrast, urocortin-2 administration in NRVM undergoing in vitro I/R inhibits SOCE and prevents I/R-induced protein overexpression of TRPC5 and Orai1 [13]. Taking into consideration these results, further investigations are necessary to clarify the functional role of TRPC channel increase after I/R.